The term “cancer” generally refers to one of a group of more than 100 diseases that are caused by the uncontrolled growth and spread of abnormal cells and can take the form of solid tumors, lymphomas and non-solid cancers such as leukemia. Unlike normal cells, which reproduce until maturation is attained and then only reproduce as necessary to replace wounded cells, cancer cells grow and divide endlessly without differentiating to mature, functional cells, crowding out nearby cells and eventually spreading to other parts of the body.
The most common sites in which cancer develops include the skin, lungs, female breasts, prostate, colon, rectum, bladder, uterus, blood-forming tissues, and lymphatic system. Cancer cells that have developed at one of these sites will grow rapidly into a malignant tumor, invading and destroying nearby tissues. Malignant cancer tumors will eventually metastasize, or spread to other parts of the body, unless their progression is stopped.
Cancers are easier to treat and cure if they are discovered and treated prior to metastasis. The survival of a patient with cancer is generally influenced by the stage at which the cancer is diagnosed. The stage, generally categorized as 1–4, is determined by the extent of disease, with stage 1 cancers being those that are small and not invading the surrounding tissues, while stage 4 cancers have established tumors in tissues other than the organ in which the cancer arose. Once cancer cells metastasize by leaving a tumor, they will travel through the bloodstream or lymphatic system to other parts of the body, where the cells begin multiplying and developing into new tumors. This sort of tumor progression makes cancer dangerously fatal. Although there have been great improvements in diagnosis, general patient care, surgical techniques, and local and systemic adjuvant therapies, most deaths from cancer are still due to metastases that are either resistant to conventional therapies or are undetected by current diagnostic methods.
The majority of diagnostic methods depend on microscopic observation of tissue biopsies. Many biopsy methods are invasive and require surgical removal of tissue for analysis.
Other useful methods for detecting cancer tissue in an animal include the use of positron emission tomography (PET scan). This method takes advantage of the increased uptake and retention by malignant cells of glucose and uses an 18F-labeled glucose derivative (FDG, 18F-2-fluoro-2-deoxyglucose). This glucose derivative, lacking a hydroxy group at the 2-position, cannot be further metabolized by the cells and is simply accumulated in the cells. This method of detection reveals live, growing tumor cells and therefore has advantages over anatomic detection methods which show abnormal structures but are insensitive to the viability of these abnormal tissues. While PET scanning is quite useful to image the entire patient for cancer, it requires expensive and cumbersome equipment for detection and construction of the positron used for the image. Accordingly, PET scanning cannot be used for the detection of cancer in many clinical settings, such as in the physician's office during the time of physical examination or in the operating room at the time of surgery.
Detection of a skin cancer such as melanoma has typically been through physical examination of the skin followed by biopsy of selected lesions suspected to be cancerous. Drawbacks to this procedure reside in the experience of the examiner, and errors in diagnosis can be life threatening. In instances where cancers are missed and then spread beyond the original site of disease, mortality can increase. Conversely, some skin lesions are biopsied which are not cancerous, and the patients are thus subjected to unnecessary harm. In some cases, biopsy samples are taken from the face, leading to cosmetic debility.
For those instances in which a patient has been diagnosed with cancer, the physician generally determines if the cancer can be removed, or resected, by surgery. Patients who have cancer that has not spread beyond a local area, stage 1 or 2, frequently may be cured by completely resecting the tumor. Prior to the surgery, various images of the tumor are obtained such as X-rays, CT scans, MRI scans or PET images. These tests provide guidance for surgery, but at the time of surgery, these images cannot be generated in real time to guide the surgeon to the tumor. As a result, the surgeon must use the unaided senses of sight and feel to determine the location and extent of the tumor.
In some instances, the surgeon will obtain biopsy samples in the area of the resected tumor prior to completing the operation. These samples are examined under the microscope to determine if all of the cancer has been removed. However, this procedure is often not conducted, as it requires a highly trained pathologist to be present at the surgery and to rapidly analyze the tissue sample while the patient remains on the operating table. If this analysis is used and the cancer remains in the patient, the surgeon continues with unaided senses to try to resect any residual tumor. Unfortunately, despite such efforts, residual tumor will be left inside the patient about 15–25% of the time. Studies have shown that these patients are at greater risk of dying of the cancer than those that have the tumor completely resected. Because of this, these patients require further, often debilitating, costly therapy in an attempt to arrest and treat the cancer left in the patient at the time of surgery.
Screening for tumors in the colon or lung is currently carried out by endoscopy using white light and a video capture screen. Due to the native fluorescence of lung tumor tissue, a special adapter for the endoscope is used to detect this autofluorescence, thereby enabling the observer to detect smaller tumors at an earlier time. However, even with this enhanced method of screening, smaller tumors and cancer cells can go undetected.
To image cancer tissue at the time of screening or at the time of surgery, attempts have been made to use radioactive isotopes or photosensitizers linked to targeting entities such as monoclonal antibodies. These detection methods are limited in that they cannot be used in the general physician's practice for screening large numbers of patients nor can they be used at the time of surgery to locate the residual tumor. Other detection methods are described in U.S. Pat. Nos. 6,256,530, 6,091,985, 6,083,487; EP patent publication No. 0588994 A1; and PCT patent publication Nos. WO 96/10363 and WO 93/13403.
What is needed are methods and reagents for detecting cancer tissue, including tumors, non-solid cancers, and cancer cells, that are convenient, without the drawbacks of the methods and reagents noted above, and that are widely applicable in a variety of clinical settings, including surgery. The present invention provides such methods, as well as compounds and compositions useful in the methods.